Blinatumomab has shown efficacy in B-cell malignancies.
1, 2, 3
Rapid clearance of peripheral B cells has been demonstrated, resulting in sustained
B-cell depletion throughout the treatment period.
1, 2, 3
This report describes serum immunoglobulin levels during and after blinatumomab treatment
in a phase 2 study in patients with minimal residual disease (MRD) of B-precursor
acute lymphoblastic leukemia (ALL).
2,3
The study followed an open-label, multicenter, single-arm, phase 2 design. Study details
and primary analysis data have been described previously.
3
Briefly, patients with positive MRD status (>10−4 detectable blast cells using quantitative
PCR) at any time after induction and consolidation therapy according to German multicenter
study group for adult ALL (GMALL) protocols were eligible. The primary objective was
to determine the efficacy of blinatumomab in patients with MRD-positive B-precursor
ALL. Patients received blinatumomab as a continuous intravenous infusion at a dose
of 15 μg/m2/day over 4 weeks, followed by a 2-week treatment-free period (6-week cycles).
For patients with an allogeneic donor, an allogeneic hematopoietic stem cell transplantation
(HSCT) was offered at any time after the first 6-week cycle. Responders could receive
three additional consolidation cycles of blinatumomab treatment. Between May 2008
and November 2009, 21 patients with MRD-positive B-precursor ALL were treated.
Serum immunoglobulins IgM, IgG, IgA and IgE have a central role in the humoral immune
response by binding to extracellular pathogens, thereby activating the complement
system along with effector cells, which ultimately leads to pathogen eradication.
4
Whereas serum IgM antibodies are mainly produced during a primary immune response
by plasma cells originating from activated naive B cells, IgG, IgA, and IgE are also
secreted in large amounts during secondary immune responses by plasma cells originating
from activated memory B cells. Most long-lived antibody-based immunity against invading
pathogens is provided by serum IgG and mucosal IgA. Hence, therapy-induced depletion
of CD19-positive B cells and plasma blasts, and associated subsequent decline of plasma
cells can result in a long-term decrease of serum immunoglobulin concentrations, which
recover only after regeneration of naive and memory B cells from CD19-negative hematopoietic
B-cell progenitors. Patients receiving B-cell–depleting therapies may therefore be
susceptible to severe infections during and after treatment.
In our phase 2 study, IgM, IgG, IgA and IgE levels were monitored during a follow-up
time ranging from 255 to 1605 days (median, 457.5 days) in six patients with MRD-positive
B-precursor ALL who did not receive HSCT after blinatumomab treatment. Four of the
six patients had Philadelphia chromosome (Ph)-negative ALL; two had Ph-positive ALL.
After completion of blinatumomab treatment, the four patients with Ph-negative ALL
did not receive any further treatment for their disease, whereas the two patients
with Ph-positive ALL received tyrosine kinase inhibitors. One of the two patients
with Ph-positive ALL had no MRD response at the end of blinatumomab treatment (Table
1). The five responders received blinatumomab for a median of 154 days (infusion period
plus treatment-free period); the nonresponder was treated for 287 days. Three patients
entered the study with an IgA level, four with an IgG level, and two with an IgM level
below normal range. The most pronounced immunoglobulin decrease was observed for IgA,
with a decline to 6% (range, 6–39%) of baseline in response to blinatumomab treatment
(Figures 1a–d; Table 1). The lowest levels of IgM and IgG were 12% (range, 12–45%)
and 29% (range, 29–101%) of baseline, respectively. In the five responders, the median
time to lowest level was 168 days for IgA, 126 days for IgM, and 260 days for IgG.
In the nonresponder, this time was 112 days for IgA, and 245 days for IgM. IgG levels
in the nonresponder did not decrease in response to blinatumomab treatment. None of
the five responders showed a return of serum IgA levels to baseline after blinatumomab
treatment, but in two responders the IgA recovery exceeded 50% of baseline. One of
the five responders showed a recovery of both serum IgG and IgM levels to above baseline,
and IgG and IgM recovery exceeded 50% in three and four of the other responders, respectively.
The nonresponder presented with less than 50% recovery of both IgA and IgM, whereas
serum IgG levels were not decreased by blinatumomab treatment.
Immunoglobulin levels and isotype recovery sequence (IgM>IgG>IgA) in responders correlated
with the expected mode of action of blinatumomab, with initial B-cell depletion leading
to decreased immunoglobulin levels during and after treatment and a subsequent return
of IgM-secreting plasma cells originating from newly developed naive B cells. However,
in the nonresponding patient, no reduction of IgG levels and a <50% recovery of IgM
levels were observed, suggesting incomplete depletion of plasma blasts during, and
diminished return of naive B cells after, blinatumomab therapy. As described above,
patients in the current study had hypogammaglobulinemia at study entry, stemming from
prior front-line chemotherapy and/or the underlying ALL. Chemotherapy has known suppressive
effects on immunoglobulin levels, with IgM and IgG typically showing the greatest
decrease after treatment.
5
Vincristine and prednisone appear to have a major role specifically in the drop of
IgG levels.
5
Chemotherapy dose reductions can lessen immunoglobulin level decreases and support
recovery.
5
As CD19, but not CD20, expression is maintained on plasma blasts, anti-CD19 antibodies
are predicted to induce a more profound decrease of immunoglobulin levels than anti-CD20
antibodies.
6
However, extensive clinical experience has shown that the anti-CD20 monoclonal antibody
rituximab may decrease serum levels of immunoglobulins across various disease settings.
For example, in patients with anti-neutrophil cytoplasmic autoantibody-associated
vasculitis, rituximab may exacerbate a cyclophosphamide-induced decline of immunoglobulin
levels.
7
Similarly, data from two patients with idiopathic thrombocytopenic purpura and pre-existing
primary antibody deficiency, who presented with recurrent infections immediately following
rituximab therapy, suggest exacerbation of the underlying immune deficiency.
8
In a study of patients with newly diagnosed aggressive B-cell lymphoma, hypogammaglobulinemia
was present at the end of chemotherapy treatment but resolved 12 months later. However,
addition of rituximab was associated with a more pronounced decline in immunoglobulin
levels than chemotherapy treatment alone, and that decline was sustained 12 months
after cessation of therapy.
9
A cross-study analysis of data from 211 patients with B-cell lymphoma who received
rituximab treatment showed that hypogammaglobulinemia developed in 38.5% and symptomatic
hypogammaglobulinemia (after multiple courses of treatment) in 6.6% of patients.
10
Two case reports have described hypogammaglobulinemia that lasted for 6–7 years after
completion of rituximab-based treatment in patients with follicular lymphoma.
11,12
In one patient, who had normal immunoglobulin concentrations at treatment start, the
level of IgG dropped to below 100 mg/dl, and both IgA and IgM remained undetectable
for 6 years after treatment stop, despite recovery of peripheral B-cell counts.
12
A second patient presented with pan-hypogammaglobulinemia and a history of recurrent
sinus infections 7 years after the completion of therapy. The symptoms resolved completely
in response to monthly intravenous immunoglobulin treatments.
11
Finally, rituximab has also been shown to delay immunologic recovery after autologous
transplantation, with low IgG levels at 2 years post transplantation.
13,14
The data from our phase 2 study show that blinatumomab-mediated depletion of B cells
and plasma blasts is reflected in decreased serum concentrations of immunoglobulins
during and after treatment. Whereas naive B cells tended to be regenerated soon after
treatment, as suggested by recovery of IgM levels, memory B cells and plasma cells
might take longer to reappear, based on the observation that recovery of IgG and IgA
levels was delayed after treatment. Infections associated with B-cell–depleting therapies
may occur during and after treatment until full recovery of IgG levels, despite prior
normalization of peripheral B-cell counts owing to regeneration of naive, but not
memory, B cells. In the present study, grade 3 infections, regardless of causal relationship
to blinatumomab, were reported in four out of the 21 patients (19%), with two (9.5%)
cases assessed as related to blinatumomab treatment. No infection-related deaths occurred.
Similarly, the rate of grade 3 or 4 infections during rituximab maintenance therapy
for the treatment of non-Hodgkin lymphoma was stated as 9.7%.
15
A review of blinatumomab data along with rituximab data available in the literature
does not suggest notable differences in the long-term recovery of serum immunoglobulin
levels. Of note, it appears that rituximab therapy may cause a sustained reduction
of immunoglobulin concentrations in serum despite the return of peripheral B cells,
suggesting a similar regeneration pattern as that proposed to follow blinatumomab
treatment. Additional depletion of plasma blasts by blinatumomab, but not by rituximab,
is not expected to be an issue as these cells are comparably short-lived and, therefore,
unable to sustain normal immunoglobulin levels throughout and after treatment. These
cells, once again, have to differentiate out of regenerated naive and memory B cells
after treatment.
In summary, baseline and periodic monitoring of immunoglobulin levels may be considered
in patients who receive antibody therapies against B-cell targets, such as blinatumomab.
Their suppressive effect on immunoglobulin levels appears to be more pronounced than
the suppressive effect of chemotherapy. In patients with severe infections and low
serum IgG concentrations, IgG substitution treatment should be considered according
to local guidelines.